The decarboxylation of ornithine to putrescine, a reaction catalyzed by the enzyme ornithine decarboxylase (ODC), is the first step in the biosynthesis of the polyamines known as spermidine and spermine. Spermidine is formed by the transfer of an activated aminopropyl moiety from S-adenosyl S-methyl homocysteamine to putrescine, while spermine is formed by the transfer of a second aminopropyl group to spermidine. S-Adenosyl S-methyl homocysteamine is formed by the decarboxylation of S-adenosylmethionine (SAM), a reaction catalyzed by the enzyme S-adenosylmethionine decarboxylase (SAM-DC).
The polyamines, which are found in animal tissues and microorganisms, are known to play an important role in cell growth and proliferation. The onset of cell growth and proliferation is associated with both a marked increase in ODC activity and an increase in the levels of putrescine and the polyamines. Although the exact mechanism of the role of the polyamines in cell growth and proliferation is not known, it appears that the polyamines may facilitate macromolecular processes such as DNA, RNA, or protein synthesis. Polyamine levels are known to be high in embryonic tissue; in the testes, ventral prostrate, and thymus; in tumor tissue; in psoriatic skin lesions; and in other cells undergoing rapid growth or proliferation.
Since putrescine is the precursor of both spermidine and spermine, it is apparent that blockade of the conversion of ornithine to putrescine, such as by inhibition of ODC, should lower intercellular polyamine levels and should provide a wide range of useful physiological effects. Inhibitors of ODC should, thus, provide a means for treating infections caused by the proliferation of certain microorganisms in which the polyamines are essential for replication; for treating certain animal diseases and disorders associated with rapid cell proliferation, such as malignent or non-malignent tumors, psoriasis, and prostatic hypertrophy; and for interrupting early embryogenesis in female mammals (contragestational activity).
It is apparent from the above that non-toxic inhibitors of ornithine decarboxylase would be useful pharmacological agents having a potentionally wide range of uses.
We have disclosed in U.K. Patent Specification No. 2001960A that inter alia compounds of the following Formula A are inhibitors of ornithine decarboxylase: ##STR3## wherein:
R.sub.a represents hydrogen or R.sub.2 where R.sub.2 is as defined below;
R.sub.b represents hydrogen or R.sub.2 where R.sub.2 is as defined below;
R.sub.2 represents C.sub.2 -C.sub.5 alkylcarbonyl, C.sub.2 -C.sub.5 alkoxycarbonyl, or --COCH(R.sub.6)NH.sub.2, where R.sub.6 represents hydrogen, C.sub.1 -C.sub.4 alkyl, benzyl or p-hydroxybenzyl;
R.sub.c represents --COR.sub.3, where R.sub.3 represents hydroxy, C.sub.1 -C.sub.8 alkoxy, --NR.sub.4 R.sub.5 where R.sub.4 and R.sub.5 independently represent hydrogen or C.sub.1 -C.sub.4 alkyl, or --NHCH(R.sub.6)CO.sub.2 H, where R.sub.6 is as defined above; and
p represents 1 or 2.
Further, we have disclosed in U.K. Patent Specification No. 2003876A that the analogues of said compounds of Formula A in which R.sub.c represents hydrogen are likewise ornithine decarboxylase inhibitors.